Respiratory-chain deficiency presenting as diffuse mesangial sclerosis with NPHS3 mutation

Area of Science:

• Genetics
• Molecular Biology
• Pediatric Nephrology

Background:

• Mitochondrial cytopathies can manifest in the kidneys, but nephrotic syndrome is an exceptionally rare presentation.
• Respiratory-chain disorders, particularly cytochrome oxidase (COX) deficiency, are seldom associated with nephrotic syndrome.

Observation:

• A 9-month-old boy presented with steroid-resistant nephrotic syndrome, followed by suspected mitochondrial cytopathy.
• Renal biopsy showed diffuse mesangial sclerosis; initial genetic analysis suggested a PLCE1 mutation.
• Ocular, neurological, and sensorineural hearing deficits, alongside muscle tissue analysis revealing respiratory chain complex IV deficiency, strengthened the suspicion of mitochondrial disease.

Findings:

• The patient exhibited a complex phenotype, not typical for primary COX deficiency, but resembling mutations in COX10.
• This is the first reported case associating a PLCE1 mutation with COX deficiency.
• No pathogenic COX10 mutations were found, indicating PLCE1 deficiency might cause secondary COX deficiency, or an unidentified recessive gene mutation underlies the mitochondriopathy.

Implications:

• This case expands the known clinical spectrum of mitochondrial cytopathies and PLCE1-related disorders.
• It highlights the importance of considering mitochondrial dysfunction in pediatric nephrotic syndrome with multi-system involvement.
• Further research is needed to elucidate the genetic basis and pathogenic mechanisms linking PLCE1, COX deficiency, and nephrotic syndrome.